*Purpose: Kidney transplant recipients (KTRs) are highly vulnerable to severe COVID-19, however are poorly protected by vaccination. Additional vaccine doses have achieved limited improvements in serological neutralisation or T cell response. A novel strategy to boost vaccine response is needed.

*Methods: KTRs (n=80) and healthy cohabitants (HCs; n=80) were recruited from a transplant centre in South Australia to undergo a 2-dose vaccination schedule with BNT162b2 or ChAdOx1. KTRs were most commonly receiving the standard-of-care (SOC) triple therapy: tacrolimus, mycophenolate mofetil, prednisolone. Following 2 vaccine doses (median 21 days; IQR 21-24), spike-specific IgG and T cell responses (by IFNγ ELISpot) were measured to assess vaccine immunogenicity, and live virus neutralisation and anti-receptor binding domain (RBD) IgG (Elecsys, Roche) were evaluated as correlates of protection from infection and disease. In an extended cohort comparing SOC (n=15) and sirolimus-inclusive (n=15) protocols, function and phenotype of antigen-specific T cells were further interrogated by flow cytometry.

*Results: Vaccine immunogenicity was profoundly reduced in KTRs, with a >1,000-fold lower median anti-spike IgG titre, and >10-fold lower median antiviral T cell response relative to HCs. Thresholds for protective anti-RBD IgG (100 U/mL) and serological neutralisation (50% neutralisation at a serum dilution of 1/40) were achieved by 6.7% and 10.9% of KTRs, respectively, and by 100% of cohabitants. In an extended cohort, patients on mTOR inhibitors (mTORi; sirolimus or everolimus) achieved 4-fold higher rates of serological neutralisation than those on SOC therapy (34.6% vs 7.9%). Remarkably, sirolimus use was associated with a median antiviral T cell response 55-fold greater than SOC therapy, and 5-fold greater than HCs. SARS-CoV-2-specific CD4⁺ and CD8⁺ T cells in these patients were highly polyfunctional and formed robust central memory out to 3 months post second vaccine dose.

*Conclusions: These data underscore priority vaccination of cohabitants as an effective strategy to protect KTRs, and support a randomised controlled trial of immunosuppression modification with sirolimus as a strategy to directly improve vaccine responses in KTRs.

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